Although there have been significant recent gains into our understanding of what causes Inflammatory Bowel Disease (IBD), there are voids in our knowledge and treatment options may be limited for certain patients. The mast cell is an effector immune cell that resides in the intestine and plays an important role in innate immunity. Although it has been thought to be important based on its increased presence in inflamed segments of intestinal tissue, its role is largely unknown. I have determined that a mediator released from activated mast cells, mouse mast cell protease-6 (mMCP- 6), plays an essential pro-inflammatory role in chemically-induced colitis in mice. The human ortholog to mMCP-6 is Tryptase-1 which is the dominant mast cell tryptase in humans. Based on published studies from our group and my preliminary data, I hypothesize that mMCP-6 acts to alter the permeability of the epithelial barrier and to bring neutrophils to the site of inflammation. I willuse strains of mice we have created to lack expression of mMCP-6 in various colitis models, in vitro studies using cultured mast cells and epithelial cells, and recombinant mouse and human mast cell tryptase to extensively study the mechanism of action of mast cell tryptase in colitis. I also will test an inhibitor of mMCP-6 which may have future therapeutic significance for patients with IBD. I will perform these studies in an Institution where every resource is available to me including facilities, mentors, collaborators, and advisers. In this environment and with the guidance of my mentors and collaborators, I will be poised to attain my goal of becoming an independent investigator. PUBLIC HEALTH RELEVANCE: Mast cells are important in allergy but they are also important to protect us from infections. Mast cells can release a substance called tryptase that I have found makes inflammation worse in certain mouse models of colitis. I propose an in depth study to see how mast cell tryptase works which will lead to new understanding for what drives inflammation in patients with Inflammatory Bowel Disease. Furthermore, I will test a drug that is designed to block the effects of mast cell tryptase and could provide a novel treatment option to treat colitis.